CS268171B2 - Method of phenoxyalkanoltriazoles' derivatives production - Google Patents

Abstract

Compounds of the formula <IMAGE> in which X represents hydrogen, fluorine, chlorine, bromine, C1-C3-alkyl, C1-C3-alkoxy, trifluoromethyl, phenyl or phenoxy, m is an integer from 1 to 3, it being possible for the individual atoms or groups to be identical or different, if m is greater than 1, and n denotes an integer from 2 to 6, are prepared by reaction of alkene oxides of the formula <IMAGE> with triazole.

Description

(57) A method for producing compounds of formula (I) wherein X is hydrogen, fluoro, chloro, bromo, C 1 -C ₃ -alkyl, C 1 -C ₃ alkoxy, trifluoromethyl, phenyl or phenoxy, m is an integer from 1 to 3, wherein when m is greater than 1, the individual atoms or groups are the same or different and n is an integer from 2 to 6, in the form of their most pure diastereomers, characterized in that the alkene oxide of the formula II in the form of its maximum pure E- or Z-isomer acts with triazole in the presence of an acid amide and an alkaline compound at a temperature of from 130 to 230 C. The produced compounds are used as fungicides.

2G8 171 Italy (11) (13) B2 (51) Int. Cl. ⁴ C 07 D 249/08

(AND)

The present invention relates to a process for the preparation of phenoxyalkanol triazoles derivatives in the form of their maximum pure diastereomers, to intermediates used in the process, and to a process for the preparation of intermediates in the form of their maximum pure isomers.

It is already known to use phenoxyalkanol triazole derivatives, for example 8- (2-fluorophenoxy) -4- (1,2,4-triazol-1-yl) -3-hydroxy-2,2-dimethyloctane as fungicides (EP 40 350). Due to the two chiral centers in the ee molecule, these compounds occur in the form of optical isomers and as diastereomers. The fungicidal effect of diastereomeric pairs of enantiomers is generally not the same, so there is interest in producing more effective diastereomers. It is already known that more efficient distereomers can be produced by selective reduction of the corresponding triazolyl ketones (DE 33 21 023.3). However, the chemical yields achieved and the purity of the diastereomeric isomers achieved are not always satisfactory.

It has now been found that the compounds of formula I

in which .

X represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy group, a trifluoromethyl group, a phenyl group or a phenoxy group; m represents an integer from 1 to 3; when m is greater than 1, the groups are the same or different from each other, and n is an integer from 2 to 6, in the form of their maximum pure diastereomers by obtaining the alkenoxide of the formula II

(CH ₉ )

П

(II) in which

X and m have the meanings given above, in the form of the maximum pure E- or Z-isomer thereof by triazole in the presence of an acid amide and an alkali compound at a temperature of from 130 to 230 ° C.

The maximum pure diastereomer contains 95 t or more by weight of the diastereomers based on the total diastereomer content.

C 1 -C 3 alkyl is, for example, methyl, ethyl, propyl, isopropyl.

C 1 -C 3 alkoxy is, for example, methoxy, ethoxy, propoxy and isopropoxy.

The reaction is carried out in the presence of alkali metal or alkaline earth metal hydroxides or comparable alkaline compounds, for example sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, in acid amides, in particular N-methylpyrrolidone or dimethylformamide, as a diluent. The reaction is carried out at temperatures between 130 and 230 ° C. Surprisingly, the spatial orientation of the various substituents at the chiral centers remains unchanged in this reaction. Thus, the spatial structure of the end product is the same as that of the alkene oxide used for the reaction. In this way, the end products of a defined spatial structure can be obtained in a simple reaction. With a good yield based on the chemical reaction, at least 95% of the diastereomer is smoothly obtained relative to the isomer content.

The alkene oxide required for the reaction is obtained by oxidizing an alkene of formula III

(Ш) in which

X and m are as defined above, in the form of their maximum pure E- or Z-isomer by treatment with an organic peracid in the presence of an organic liquid at a temperature of -10 to +30 ° C.

The organic peracid is, for example, m-chloroperbenzoic acid or peracetic acid.

The reaction is carried out, for example, in chlorinated hydrocarbons, in particular methylene chloride, when m-chloroperbenzoic acid is used as the oxidizing agent, or in protic solvents, especially in aqueous acetic acid, when peracetic acid is used as the oxidizing agent.

In the case of peracetic acid oxidation, it is possible to produce the peracetic acid in situ from hydrogen peroxide and acetic acid.

The oxidation is carried out at temperatures from -10 ° C to 30 ° C, in particular at temperatures from +15 to + 25 ° C.

The two reaction steps, i.e. the oxidation and the reaction with the triazole, are carried out with a very good chemical yield with at least 95% sc with selectivities relative to the isomers. In this way, a pair of RS / SR enantiomers of formula I is obtained readily from the E-alkenes of formula III and a pair of RR / SS enantiomers of formula I from the Z-alkenes of III.

The problem of diastereoselective synthesis of compounds of formula I is thus reduced to the synthesis of stereochemically uniform E- or Z-alkenes of formula III.

CS 268171 02

Alkenes of formula III (W ₅ ^{CH 3}

CH - CH - _{(CH2) n} - o

6 // 3

in which

X represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C1 -C3 alkyl group, a C1 -C3 alkoxy group, a trifluoromethyl group, a phenyl group or a phenoxy group; m represents an integer from 1 to 3; when m is greater than 1, the individual atoms or groups may be the same or different from each other, and n is an integer from 2 to 6, in the form of their maximum pure E-isomers are obtained by heating a compound of formula IV

(IV).

in which

X represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy group, a trifluoromethyl group, a phenyl group or a phenoxy group; m represents an integer from 1 to 3; greater than 1, then the individual atoms or groups may be the same or different from each other, n represents an integer from 2 to 6, and

R is -COCH3 or -CSSCH3, at a temperature of 200 to 400 ° C or a temperature of 100 to 300 ° C.

In the case of acetals, the substance is heated as such or in a high-boiling inert diluent to a temperature of 200 to 400 ° C. In carrying out the reaction in mass sc, it mainly uses temperatures of from 250 to 250 ° C

350 ° C. In the case of xanthates, it is sufficient to heat the compound to temperatures of 100 to 300 ° C. The process is carried out in a high-boiling diluent or the substance is heated as such. For carrying out the reaction in the mass, temperatures from 150 to 250 ° C are mentioned as optimal temperatures. The resulting alkenes of formula III are distilled at atmospheric pressure or under reduced pressure. The chemical yields are between 90 and 100 I. The selectivity based on isomers is at least 95%. Acetals or xanthogenates can be prepared in a conventional manner from the alcohols described in DE 34 00 829.

Another method for producing alkenes of formula III in the form of their maximum pure E-isomers is to treat alkenes of formula III present in the form of their Z-isomers with shortwave light in the presence of diphenyldisulfide and a hydrocarbon.

The hydrocarbon is, for example, a C 5 -C 8 alkane or cycloalkane such as pentane, hexane, cyclohexane, heptane or octane. _E

For example, shortwave light is light that has spectral scattering of a high pressure mercury lamp. The exposure to shortwave light can be carried out at conventional temperatures, for example at room temperature (20 ° C) or at any other temperature.

The alkenes of the formula III in the form of their maximum pure Z-isomers are obtained by reacting pivalaldehyde of the formula (CH ₃ > ₃ CCl 10 with a compound of the formula

(V) in which

X is hydrogen, fluoro, chloro, bromo, (C 1 -C 3) alkyl, (C 1 -C 3) alkoxy, trifluoromethyl, phenyl or phenoxy, m is an integer from 1 to 3, That m is greater than 1, then the individual atoms or groups may be the same or different, and n is an integer from 2 to 6.

This reaction is carried out in a salt-free environment, i.e. in polar aprotic solvents, in the absence of dissolved metal cations (cf. H.O. House, Modern Syntetic Reactions, 2nd Edition 1972, p. 707 et seq.).

Suitable solvents for this reaction are linear or cyclic ethers, in particular tetrahydrofuran. The reaction proceeds at temperatures from 20 ° C to 100 ° C. When tetrahydrofuran is used as the solvent, a particularly preferred temperature range is from 50 to 60 ° C (reflux temperature). '

Upon completion of the reaction and separation of the triphenylphosphine oxide, the Z-alkene of formula III is obtained in good chemical yields with a selectivity of the Z-isomers of at least 90%.

The intermediates required to produce the phosphorus derivative are known (cf. EP

350).

The following examples illustrate the invention. However, these examples do not limit the scope of the invention in any way.

CS 268171 β2

Examples:

The production steps of the 3R, 4S / 3S, 4R-enantiomeric pair of 8- (2-fluorophenoxy) -4- (1,2,4-triazol-1-yl) hydroxy-2,2-dimethyloctane are illustrated in more detail below. The procedure described in the examples can be used to synthesize the compounds listed in the tables.

Production of аtеtat:

g (0.23 mol) of the octanol derivative was heated in 200 ml of acetic anhydride with 1 ml of concentrated hydrochloric acid at reflux for 2 hours. Distillation yielded acetate after removal of the acetic acid / acetic anhydride premix fraction. Boiling point: 135 ° C / 6.7 Pa.

Yield: 65 g.

@ 1 H-NMR (CDCl3): .delta.

0.9 (s, 9H), 1.25- 4.75 (double d, 1H), 1.65 (m, 6H); 1.8 (m, 2H); 6.8-7.1 (m, 4H). 2.05 (s, 310, 4.0 (t, 2 H) Table 1

CS 26-171 B2

Number ^X mm n physical data IV / 1 2-F 4 MW: 135 ° C / 6.7 Pa IV / 2 2-C1 4 IV / 3 2-C » ₃ 4 IV / 4 4-F 4 IV / 5 4-C1 4 IV / 6 _4-CH3 4 IV / 7 2,4-Cl ₂ 4 IV / 8 2,4,6-Cl ₃ 4 Production xanthogenate:

1. NaH

2. EN ₂

-------->

CH ₃ J

To 58 g (0.23 mol) of the octanol derivative dissolved in toluene was added portionwise an equivalent of sodium hydride. To complete the formation of the alkoxide, the reaction mixture is refluxed for hours. The reaction mixture was then allowed to cool to 20 ° C, and carbon disulfide dissolved in 100 ml of diethyl ether was added dropwise. About 1 hour after the carbon disulfide addition was complete, about 1.5 equivalents of methyl iodide was added dropwise to the reaction mixture, and the reaction mixture was heated at reflux for 2 hours. After filtration and evaporation of all readily volatiles under reduced pressure, 77 g of xanthogenate remained as a nearly colorless oil.

¹ H NMR Spectrum (CDCl 3): 0.95 (s, 9H), 1.3-1.9 (m, 8H), 2.55 (s, 3H),

4.0 (t, 2H), 5.72 (double d, 1H), 6.8-7.3 (m, 411).

IR spectrum (coating): 2951, 1507, 1456, 1281, 1223, 1206, 1110, 1051 cm -1 F

Table 2

В

Number X m n physical data IV / 9 2-F 4 NMR / IR (see example) IV / 10 2-C1 4 IV / 11 _2-CH3 4 IV / 12 4-F 4 IV / 13 4-C1 4 IV / 14 _4-CH3 4 IV / 15 ^2/4 “ ^C1 2 4 IV / 16 2,4,6-Cl ₃ 4

Production of alkene from acetate:

(Ula / L) g (0.26 mol) of IV / 1 acetate was heated in a metal bath to 350 ° C. Acetic acid and then alkane IIIa / 1 are distilled off through the loaded column. 64 g of alkene are obtained, b.p. 295 DEG C. at atmospheric pressure. It is easy to identify the E-configuration of the double 13 bond by the position of carbon atoms 3 and 4 in the C-NMR spectrum (in deuterochloroform):

C-3 142.1 ppm

C-4 124.2 ppm.

Production of alkene from xanthogenate:

g of xanthogenate IV / 9 (0.057 mol) was heated to a temperature of ca.

200 ° C. The nitrogen stream expels 10.3 g of alkene IIIa / l in 2 hours, which is collected in the receiver. The double bond configuration can be determined by the ¹³ C-NMR (spectrum) unambiguously as the E configuration:

C-3 142.1 ppm

C-4 124.2 ppm.

Production of alkene IIIa / 1 by isomerization:

shortwave radiation

- diphenyldisulfide

(IIIa / 1) g (0.132 mol) of Z-8- (2-fluorophenoxy) -2,2-dimethyloct-3-one IIIb / 1 sc was dissolved in 400 ml of cyclohexane. 2.83 g (0.013 mol) of diphenyldisulphide are then added to the obtained solution and the solution is purged with nitrogen for 30 minutes. Then the solution is irradiated with a high pressure mercury lamp (125 W - Philips HPK) through a duran filter at an internal temperature of 35 ° C. After 3 hours of irradiation, the conversion was 95%. The reaction solution was filtered and distilled through the column. 25.8 g of E-8- (2-fluorophenoxy) -2,2-dimethyloct-3-ene (IIIa / 1) having a boiling point of 90 DEG C./20 mbar are obtained.

Table 3a

configuration E

Number X m n physical data IIIa / 1 2-F 4 t.v. 295 [deg.] C IIIa / 2 2-C1 4 IIIa / 3 ^2_CH 3 4 IIIa / 4 4-F 4 IIIa / 5 4-C1 4 IIIa / 6 4-CH 3 4 IIIa / 7 2,4-Clj 4 IIIa / 8 2,4,6-Cl ₃ 4

Production of alkene IIIb / 1:

® O (C _O H _{5) 3} P - CH _{(CH2) 4}

CS 268171 в2

(IIIb / 1)

261.5 g (0.5 mol) of triphenyl- [5- (3-fluorophenoxy) pentyl] phosphonium bromide were prepared from equimolar amounts of triphenylphosphine and 5- (2-fluorophenoxy) bromopentane at 130-140 ° C. After cooling, the solidified melt is milled and suspended in 1000 ml of tetrahydrofuran. 2a Cooling was added dropwise with 370 ml (0.55 mol) of a 1.5 M solution of butyllithium in n-hexane. The reaction temperature is maintained at 20-30 ° C and the reaction mixture is stirred for an additional 1 hour. A solution of 43 g (0.5 mol) of pivalaldehyde in 150 ml of tetrahydrofuran is now added dropwise to the resulting brown solution over about 30 minutes. The reaction mixture was stirred at 20 ° C for 20 hours and then refluxed at 60 ° C for 24 hours until a white, granular precipitate formed.

The mixture is hydrolyzed by the addition of 2 liters of water, the organic phase is separated and the aqueous phase is extracted three more times with diethyl ether. The combined organic phases were washed twice with water, dried over sodium sulfate and evaporated. Ether (250 ml) was added to the residue and triphenylphosphine oxide precipitated. The mixture was filtered and the filtrate was distilled. 33.5 g of Z-8- (2-fluorophenoxy) -2,2-dimethyloct-3-ene of formula IIIb / 1 are obtained in the form of a colorless liquid having a boiling point of 127 DEG C./20 mbar,

Table 3b

(Illb)

Z-configuration

number ^X m n physical data IIIb / 1 2-F 4 mp: 127 ° C / 200 Pa IIIb / 2 2-Cl 4 IIIb / 3 _2-CH3 4 IIIb / 4 4-F 4 IIIb / 5 4-C1 4 IIIb / 6 4-CK ₃ 4 IIIb / 7 2,4-Cl ₂ 4 IIIb / 8 2,4,6-Cl ₃ 4

Production of alkenoxide:

perkyaellna

(IIa / 1) g (0.2 mol) of E-8- (2-fluorophenoxy) -2,2-dimethyloct-3-ene of formula IIIa / 1 is dissolved in 300 ml of methylene chloride. A solution of 39.7 g (0.23 mol) of 3-chloroperbenzoic acid in 550 ml of methylene chloride was added dropwise to the obtained solution with stirring over a period of 20 minutes, and the reaction temperature was kept at 20 ° C by cooling. A white precipitate (3-chlorobenzoic acid) was slowly formed. The reaction mixture was stirred at 20 ° C for 2 days. The starting material was then completely reacted (as analyzed by gas chromatography). For working up, the reaction mixture was stirred with 1000 ml of 10% aqueous sodium sulfate until peroxide was no longer detectable. The pH was adjusted to 7 with sodium hydroxide, the methylene chloride phase was separated and the aqueous phase was extracted once more with methylene chloride. The combined organic phases were washed twice with sodium carbonate solution and twice with distilled water, dried over sodium sulphate and evaporated on a rotary evaporator under reduced pressure at 40 ° C. 55.6 g of crude product are obtained, containing 90% of 2- [4- (2-fluorophenoxy) butyl] -3-tert-butyloxirane of the formula IIa / 1 (determined by gas chromatography). According to 1 H-NMR spectrum, the ratio of compound E: Z = 99: 1.

spectrum (deuterochloroform):

0.9 (s, 911), 1.5-1.7 (m, 4H), 1.8-1.9 (m, 2H), 2.49 (m, 1H),

2.82 (m, 1H), 4.05 (t, 2H), 6.8-7.1 (m, 4H).

CS 268171 β2

Table 4a

number ^X m n physical data IIa / 1 2-F 4 1 H-NMR (spectrum (see example)) IIa / 2 2-C1 4 IIa / 3 ² ~ ^CH3 4 IIa / 4 4-F 4 IIa / 5 4-C1 4 IIa / 6 4-CH ₃ 4 IIa / 7 2,4-Cl? 4 IIa / 8 2,4,6-Cl ₃ 4

Table 4b

Z-Conflguration number X m (lib) n physical data Ilb / l 2-F 4 IIb / 2 2-C1 4 IIb / 3 of ₃ 4 IIb / 4 4-F 4 IIb / 5 4-C1 4 IIb / 6 _4-CH3 4 IIb / 7 2,4-Cl ₂ 4 IIb / 8 2,4,6-Cl ₃ 4

CS 268171 в2

Production of triazolus derivative

Na OH

->

a pair of 3R / 4S-3S / 4R enantiomers

9.5 g (0.036 mol) of E-2- (2-fluoro-phenoxybutyl) -3-tert-butyloxirane of formula IIa / 1, about 90% by gas chromatography, 50 ml of N-methylpyrrolidone, 1.5 g (0.036 mol) of sodium hydroxide and 2.5 g (0.036 mol) of 1,2,4-triazole are heated together and stirred at 180 ° C. The reaction is monitored by gas chromatography. After 4 hours, the conversion is greater than 98%. The N-methylpyrrolidone was distilled off under reduced pressure and, after cooling, the residue was dissolved in a mixture of water and methylene chloride. The aqueous phase is extracted once more with methylene chloride. The combined methylene chloride phases are washed with water until the acid is removed, dried over sodium sulfate and concentrated. The residual brown oil (10.9 g) was dissolved hot in 150 ml of cyclohexane, stirred with 0.5 g of activated carbon for 30 minutes and filtered while hot. Evaporation of the filtrate gave 8.6 g of 8- (2-fluorophenoxy) -4- (1,2,4-triazol-1-yl) -3-hydroxy-2,2-dimethyloctane as a colorless oil which crystallized on standing . The relative ratio of diastereomers in the mixture was 1: 99 according to NMR spectrum (IR + SS): (RS + SR) = 1: 99.

87 ° C

Table 6a

pair of enantiomers 3R, 4S / 3S, 4R number X n melting point (° C)

Ia / 1 2-F 4 87 Xa / 2 2-C1 4 106 Ia / 3 _2-CH3 4 • 89-93 Ia / 4 4-F 4 126-128 Ia / 5 4-C1 4 159 Ia / 6 4-Cl < ₃ 4 128-130 Ia / 7 2,4-Clj 4 96-97 Ia / 8 2,4,6-Cl ₃ 4

Table 6b

pair of 3R enantiomers. 4R / 3S, 4S

X _m n physical data

Ib / 1 2-F 4 Ib / 2 2-C1 4 Ih / 3 _2-CH3 4 Ib / 4. 4-F 4 Ib / 5 4-C1 4 Ib / 6 _^4-CH3 4 Ib / 7 2,4-Cl ₂ 4 Ib / 8 2,4,6-Cl ₃ 4

Claims (1)

OF THE INVENTION A process for the preparation of phenoxyalkanol triazole derivatives of the general formula I in which: X is hydrogen, fluoro, chloro, bromo, (C 1 -C 3) alkyl, (C 1 -C 3) alkoxy, trifluoromethyl, phenyl or phenoxy, m is an integer from 1 to 3, when m is greater than 1, then the individual atoms or groups are the same or different, and n is an integer from 2 to 6, in the form of their most pure diastereomers, characterized in that the alkenoxide of formula II (CH ₂ ) _n - (II). in which X, n and m are as defined above, in the form of its maximum pure E- or Z-isomer, it acts triazole in the presence of an acid amide and an alkaline compound at a temperature of from 130 to 230 ° C.